Abstract
Advanced endometrial cancer continues to have a poor prognosis, due to limited treatment options, which may be further adversely impacted by obesity. Endometrial cancer stem cells have been reported to drive metastasis, chemotherapy resistance and disease relapse, but have yet to be fully characterised and no specific targeted therapies have been identified. Here, we describe the phenotype and genotype of aldehyde dehydrogenase high (ALDHhigh) and CD133+ve endometrial cancer stem cells and how adipocyte secreted mediators block the inhibitory effect of metformin on endometrial cancer stem cell activity. Ishikawa and Hec-1a cell lines were used to characterise ALDHhigh and CD133+ve endometrial cancer cells using flow cytometry, functional sphere assays and quantitative-Polymerase Chain Reaction. The comparative effect of metformin on endometrial cancer stem cell activity and bulk tumour cell proliferation was determined using an Aldefluor and cytotoxicity assay. The impact of adipocyte secreted mediators on metformin response was established using patient-derived conditioned media. ALDHhigh cells demonstrated greater endometrial cancer stem cell activity than CD133+ve cells and had increased expression of stem cell and epithelial-mesenchymal transition genes. Treatment with 0.5–1 mM metformin reduced the proportion and activity of both endometrial cancer stem cell populations (p ≤ 0.05), without affecting cell viability. This effect was, however, inhibited by exposure to patient-derived adipocyte conditioned media. These results indicate a selective and specific effect of metformin on endometrial cancer stem cell activity, which is blocked by adipocyte secreted mediators. Future studies of metformin as an adjuvant therapy in endometrial cancer should be adequately powered to investigate the influence of body mass on treatment response.
Highlights
Already the fourth most common cancer in women, the incidence of endometrial cancer is rising globally as a consequence of the escalating rates of obesity, to which up to 41% of endometrial cancersCancers 2019, 11, 653; doi:10.3390/cancers11050653 www.mdpi.com/journal/cancersCancers 2019, 11, 653 can be directly attributed [1,2,3]
ALDHhigh and CD133+ve Endometrial Cancer Cells Demonstrate Cancer Stem Cell Activity and Increased. Both Ishikawa and Hec-1a endometrial cancer cell lines contained a small proportion of cells with the ability to survive, proliferate and form three-dimensional spherical structures in non-adherent culture
The self-renewal capacity of these spheres was demonstrated by serial passaging and increased with each passage, suggesting positive selection for cancer stem cells
Summary
Already the fourth most common cancer in women, the incidence of endometrial cancer is rising globally as a consequence of the escalating rates of obesity, to which up to 41% of endometrial cancersCancers 2019, 11, 653; doi:10.3390/cancers11050653 www.mdpi.com/journal/cancersCancers 2019, 11, 653 can be directly attributed [1,2,3]. Any modest short term benefit from chemotherapy is counteracted by an ongoing risk of disease relapse after treatment is discontinued [13] This has been hypothesised to be due to the persistence of a sub-population of tumour cells referred to as cancer stem cells [14]. These progenitor stem cells have acquired the capacity for self-renewal through the accumulation of mutations in the Wnt/β-catenin, BMI1 and Hippo signalling pathways and are able to differentiate into multiple different cell types [15,16,17,18]. They form tumours when transplanted into animal models at much lower concentrations than bulk tumour cells, have increased invasion and migration capacity and are resistant to commonly used chemotherapeutic drugs, making them responsible for metastasis and disease relapse [19]
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